This is a resubmission application for the K08 Mentored Clinical Scientist Research Career Development Award for Dr. Arun Wiita in the Dept. of Laboratory Medicine at the University of California, San Francisco. Dr. Wiita completed his MD/PhD at Columbia University, including highly successful graduate work in single molecule biophysics in the lab of Julio Fernandez, PhD. Since finishing his residency in Laboratory Medicine at UCSF he has been pursuing research in apoptosis in hematologic cancers with Jim Wells, PhD. Despite moving into a very different field, Dr. Wiita has made significant progress on two major projects, one published and the other submitted. His long-term goal is to understand in greater detail how cancer cells evolve and respond to therapies, eventually resulting in new diagnostic tools to assist cancer management. The K08 award will provide Dr. Wiita with the protected time and additional training in bioinformatics, proteomics, and cancer signaling networks critical to his development as a tenure-track physician-scientist primarily devoted to laboratory research. His mentor, Jim Wells, PhD, an expert on therapeutics and cell death, and his co-mentor, Kevin Shannon, MD, an expert on hematologic malignancies, have extremely strong records of mentorship. Additional advisory committee members include Jonathan Weissman, PhD, an expert on systems biology, Al Burlingame, PhD, a pioneer of biological mass spectrometry, and Scott Kogan, MD, a physician-scientist bridging clinical and basic research in Laboratory Medicine. Including coursework and participation in seminars and conferences, Dr. Wiita has drawn on the myriad resources of the UCSF scientific community to promote his career as an independent investigator. The research proposal is centered on using emerging, systems-level technologies to address pressing issues in management of multiple myeloma, an incurable, aggressive hematologic malignancy. In Aim 1 Dr. Wiita has begun to develop a unique pipeline combining mRNA deep sequencing, ribosome profiling, and quantitative proteomics to monitor bortezomib-induced cell death in myeloma cells. These studies have already revealed extensive biological insight into translational dynamics after bortezomib exposure. Here he will expand these studies with new proteomic and analysis methods to monitor the role of post-translational modifications and cellular signaling. In Aim 2 Dr. Wiita will use the first-of-its-kind data obtained in this pipeline to develop a new quantitatie model of protein translation and translational regulation. These processes are key determinants of cellular homeostasis and regulation and also play an important role in myeloma pathogenesis. In Aim 3 Dr. Wiita will use cell and molecular biology approaches to elucidate resistance and response markers as well as combination therapeutic targets in myeloma, driven by hypotheses based on systems-level data. These studies are deeply related to the missions of the NIH and NCI as they will greatly expand our understanding of therapeutic effects in myeloma and, in the future, potentially any malignancy.